The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. Pyramidal neurons are the principal cells of the prefrontal cortex and integrate glutamatergic inputs from multiple brain regions. These excitatory neurons also receive extensive dopaminergic inputs from sub-cortical brain areas that modulate pyramidal neurons. Together, glutamatergic and dopaminergic inputs help to govern the physiological properties of pyramidal neurons and determine the function of the prefrontal cortex. The primary goal of this study is to understand how these inputs interact at the sub-cellular level in pyramidal neurons. A mechanistic approach will reveal the electrical and calcium (Ca) signals generated during synaptic transmission and integration. Ca signals control the induction of synaptic plasticity, gene expression and morphological stability of these neurons. A combination of 2-photon microscopy and 2-photon laser uncaging will be used to study these signals at individual dendrites and spines. The planned experiments will reveal the importance of different voltage-sensitive ion channels and glutamate receptors in generating Ca signals. Moreover, they will determine how dopamine receptor activation modulates these channels and receptors to influence local Ca signals. The results from these experiments will answer fundamental questions about how prefrontal pyramidal neurons integrate their synaptic inputs. Moreover, they will identify novel therapeutic targets for the debilitating neurological diseases that arise from dysfunction of these neurons. PUBLIC HEALTH RELEVANCE: The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from mice to humans. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. The proposed experiments will determine how these neurons function and identify novel treatments for these and other debilitating neurological diseases.